The main objective of this project is to better understand the contributions of dysregulation of the adaptive and innate immune system in synucleinopathies of the aging population (eg: PD, DLB, AD) and developing new therapies for PD, DLB and AD by harnessing the immune system. I arrived to NIA in July of 2016 and started to set the Molecular Neuropathology section at the LNG in October of 2016. The first task from July to October was to recruit 2 scientists to work with me on these projects. I was fortunate to recruit Dr. Changyoun Kim from my former lab at UCSD and Dr. Michiyo Iba from U Penn. Dr. KIm focuses on the in vitro aspects of the neuro-immune and therapeutics project and Dr. Iba focuses on the in vivo rodent experiments of the neuro-immune project. Upon arrival in October 2016, Drs. Kim and Iba expended most of their time on setting the lab, purchasing equipment, setting up the neuro-immune and neuropathology techniques and setting the animal colonies and protocols. Very rapidly this was achieved and by December 2016 the lab was already partially up and running and collaborations were established with Drs. Singleton, Cookson and Sen. I also brought to NIA a small colony of my Thy1-a-synuclein mice from UCSD for breeding and experiments. The animal colony was set and in addition colonies of LRRk2 mice were integrated into the work. Moreover we set in place siRNA libraries, RNA seq methods, immunocytochemistry, neuropathology, confocal imaging, EM, cell to cell transmission assays with fluorescent complementation, assays of neurotoxicity in vitro, primary neurons and microglial cell cultures, FACS analysis for immune cells, immunotherapy assays in vitro and seeding assays in vivo with synuclein and AD-tau (via stereotaxic intra-cerebral injection). All protocols and approvals are in place. By Aim and projects progress has been as follows: Project 1. Role of TLR2 as an a-synuclein receptor and TLR2 signaling in neuro-inflammation in synucleinopathies. Dr. Changyoun Kim is running this project (in collaborations with Mark Cookson). We have nearly completed the first part of this project and a manuscript was submitted to JCI. The preliminary results will be presented at SFN in Wash DC Nov 2017. 2. To determine the role of of interactions between Tau aggregates and a-synuclein, GBA and LRRK2 in the pathogenies of PD, DLB and AD. Dr Michiyo Iba is running this project (in collaboration with Mark Cookson and Ellen Sidransky. This project also investigates the contribution of p38gamma signaling in these neuro-immune pathways. The intra-cerebral injections into a-synuclein mice have been accomplished and analysis is underway. The preliminary results with the p38gamma project will be presented at SFN in Wash DC Nov 2017. A manuscript is in preparation. 3. To characterize immune cell responses in models of synucleinopathies and to develop combined active and T cell mediated immunotherapy for synucleinopathies. Dr. Changyoun Kim is running this project in collaboration with Ranjan Sen and Jyoti Sen.This project has been partially completed, a manuscript on combined immunotherapy is under re-reveiw by J Neuro. Other collaborations at LNG are with Drs. Andy Singleton, Bryan Traynor and Sonja W Scholzon FTD, DLB and MSA. We have provided brain tissues from my neuropathology collection at my former lab for WGS.